Epitope mapping by NMR of a novel anti-Aβ antibody (STAB-MAb)
Springer Nature, 2019
Online
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Alzheimer´s Disease (AD) is one of the most common neurodegenerative disorders worldwide. Excess of β-amyloid (Aβ), a peptide with a high propensity to misfold and self-aggregate, is believed to be the major contributor to the observed neuronal degeneration and cognitive decline in AD. Here, we characterize the epitope of a novel anti-Aβ monoclonal antibody, the STAB-MAb, which has previously demonstrated picomolar affinities for both monomers (KD = 80 pM) and fibrils (KD = 130 pM) of Aβ(1-42) and has shown therapeutic efficacy in preclinical mouse models of AD. Our findings reveal a widespread epitope that embraces several key Aβ residues that have been previously described as important in the Aβ fibrillation process. Of note, STAB-MAb exhibits a stronger affinity for the N-terminus of Aβ and stabilizes an α-helix conformation in the central to N-terminal region of the peptide, in addition to disrupting a characteristic salt-bridge of a hairpin structure present in fibrils. The NMR derived epitope supports the observed results from ThT-monitored fluorescence and electron microscopy experiments, in which STAB-MAb was shown to inhibit the formation of aggregates and promote disruption of pre-formed fibrils. In combination with the published in vitro and in vivo assays, our study highlights STAB-MAb as a rare and versatile antibody with analytical, diagnostic and therapeutic efficacy.
This work was partially funded by European Community’s Seventh Framework Programme FP7-SP3-People-606950 and Unidade de Ciências Biomoleculares Aplicadas-UCIBIO which is financed by national funds from FCT/MEC (UID/Multi/04378/2013) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728). The NMR spectrometers are part of the National NMR Network (PTNMR) and are supported by Infrastructure Project No 022161 (co‐financed by FEDER through COMPETE 2020, POCI, and PORL and FCT through PIDDAC).
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Epitope mapping by NMR of a novel anti-Aβ antibody (STAB-MAb)
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Autor/in / Beteiligte Person: | Posado-Fernández, Adrián ; Afonso, Cláudia F. ; Dória, Gonçalo ; Flores, Orfeu ; Cabrita, Eurico J. ; Repositório da Universidade de Lisboa |
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Veröffentlichung: | Springer Nature, 2019 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41598-019-47626-2 |
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